Oral arsenic (ATO) in low-risk myelodysplastic syndromes (MDS) failing Erythropoiesis Stimulating Agents and Luspatercept

Phase 1

Not yet recruiting

Conditions: low-risk Myelodysplastic Syndromes failing Erythropoiesis Stimulating Agents and Luspatercept (or ineligible for the latter)

Interventions: Drug: Arsenic Trioxide (ATO)

Registration Number: 2024-515311-22-00

Lead Sponsor: Groupe Francophone Des Myelodysplasies

Brief Summary: Part 1 (Phase I study): To determine the dose-limiting toxicity (DLT) of oral ATO

Part 2 (Expansion phase): To determine the erythroid response rate (HI-E) after 12 weeks oral ATO treatment

Detailed Description: Dose escalation cohort to determine the dose limiting toxicity according to a BOIN (Bayesian optimal interval) scheme.

Patients will receive one dose of study treatment (oral Arsenic (ATO)) 5d/7 for 21 days over a 28-day cycle.

Three doses of ATO will be tested (0.10 mg/kg, 0.15 mg/kg and 0.20 mg/kg), and 9 patients will be treated at each dose.

An expansion cohort at the selected dose based on DSMB recommendations will be conducted with 6 patients, for a maximum of 15 patients included at this dose level.

Tolerability will be assessed after one treatment cycle. Response will be assessed after 3 cycles of treatment. Responders may continue study treatment until progression or limiting toxicity. Limiting toxicity is defined as any grade III/IV extra-hematological toxicity or grade IV hematological toxicity lasting more than 25 days.

If there is no response, patients will stop treatment and enter the follow-up phase of the study.

Recruitment & Eligibility

Status: Authorised, recruitment pending

Sex: Not specified

Target Recruitment: 24

Inclusion Criteria

Myelodysplastic syndrome according to WHO 2022 classification

Adequate renal function defined by creatinine level less than 1.5 times the upper limit of normal and creatinine clearance ≥ 40mL/min (according to MDRD formula)

Adequate liver function defined by total bilirubin and transaminases less than 1.5 times the upper limit of normal

Patient not refractory to platelet transfusions

Diabetic patients should have well-controlled diabetes with HbA1c level ≤ 7.5% prior to inclusion

A FCBP (female of childbearing potential) for this study was defined as a sexually mature woman who: (1) had not undergone a hysterectomy or bilateral oophorectomy; or (2) had not been naturally postmenopausal (amenorrhea following cancer therapy did not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). A FCBP participating in the study must: o Have had 2 negative pregnancy tests as verified by the investigator prior to starting IP (unless the screening pregnancy test was done within 72 hours of Cycle 1 Day 1). She must have had agreed to ongoing a monthly pregnancy testing during the course of the study and after EOT. o If sexually active, agreed to have used, and been able to comply with, highly effective contraception** without interruption, 5 weeks prior to starting IP, during treatment with IP (including dose interruptions), and for 24 weeks after discontinuation of IP. **Highly effective contraception was defined in this protocol as the following (information also appeared in the ICF): Hormonal contraception (eg, birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device, tubal ligation (tying your tubes), or a partner with a vasectomy. Male subjects must: Have agreed to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (eg, polyurethane), during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions, and for at least 24 weeks following IP discontinuation, even if he had undergone a successful vasectomy.

Patient must understand and voluntarily sign informed consent form

Patient must be able to adhere to the visit schedule as outlined in the study and follow protocol requirements

Performance status 0-2 at the time of screening

Male subjects must: Have agreed to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (eg, polyurethane), during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions, and for at least 24 weeks following IP discontinuation, even if he had undergone a successful vasectomy.

Age ≥ 18 years

Patient with low-risk MDS according to IPSS-R classification (very low, low, intermediate): - non-sideroblastic who failed to achieved a response or who subsequently relapse after ESA (at Epoetin alfa 60000UI or equivalent over at least 12 weeks) without disease progression or ineligible to ESA (defined by EPO > 500UI/L) - sideroblastic who failed to achieved a response or who subsequently relapse after ESA (at Epoetin alfa 60000UI or equivalent over at least 12 weeks) or ineligible for ESA (defined by EPO >500UI/L) and who failed to achieved a response or who subsequently relapse after Luspatercept - del (5q) who failed to achieved a response or who subsequently relapse after ESA (at Epoetin alfa 60000IU or equivalent over at least 12 weeks) and who failed to achieved a response or who subsequently relapse after Lenalidomide

Transfusion dependence (at least 3 RBC required within a 16-week period and at least 2 transfusion episodes during this period)

Patient not eligible for another clinical trial

Exclusion Criteria

Severe infection or any uncontrolled severe condition

Active cancer or cancer during the year prior to trial entry other than basal cell carcinoma, or carcinoma in situ of the cervix or breast

Patient already enrolled in another therapeutic trial of an investigational drug

Known HIV infection or active hepatitis B or C

Patients with hypoxia requiring oxygen assistance

Patients with overrisk of encephalopathy (ie: vitamin B1 deficiency)

Patients taking concomitant treatment known to prolong the QT interval

Known hypersensibility to the arsenic or one excipient

Persons not affiliated to a social security system or equivalent

Persons deprived of liberty by judicial or administrative decision

Persons subject to a legal protection measure (guardianship, curatorship, safeguard of justice)

Women who are or could become pregnant or who are currently breastfeeding

Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form

Patient eligible for allogeneic stem cell transplantation

Uncontrolled hypertension

Significant cardiac disease - NYHA Class III or IV or having suffered a myocardial infarction in the last 6 months

QTcF > 460ms

Use of investigational agents within 30 days or any anticancer therapy (including IMiD) within 2 weeks before the study entry with the exception of hydroxyurea. The patient must have recovered at least a grade 1 from all acute toxicity from any previous therapy. However, patients may have received Lenalidomide, hypomethylating agent, or anti-lymphocytic serum (ALS) (but not within 4 weeks before the study entry and, for ALS, within 16 weeks before the study entry).

Use of EPO within 4 weeks before the study entry

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ATO	Arsenic Trioxide (ATO)	Oral Arsenic treatment

Primary Outcome Measures

Name	Time	Method
Part 1 (Phase I study): Dose-limiting toxicity (DLT) of oral ATO over an observation period from day 28 to day 42 following the start of cycle 1		Part 1 (Phase I study): Dose-limiting toxicity (DLT) of oral ATO over an observation period from day 28 to day 42 following the start of cycle 1
Part II (Expansion Phase): Erythroid response rate (HI-E) after 12 weeks oral ATO treatment		Part II (Expansion Phase): Erythroid response rate (HI-E) after 12 weeks oral ATO treatment

Secondary Outcome Measures

Name	Time	Method
Safety profile and tolerability measured according to CTCAE (latest version)		Safety profile and tolerability measured according to CTCAE (latest version)
Bioequivalence compared to IV ATO in terms of PK/PD		Bioequivalence compared to IV ATO in terms of PK/PD
Response to treatment will be assessed after cycle 3 according to IWG 2018 criteria		Response to treatment will be assessed after cycle 3 according to IWG 2018 criteria
Response duration measured from date of objective response to date of relapse or progression (or date of last news in absence of event)		Response duration measured from date of objective response to date of relapse or progression (or date of last news in absence of event)
Rate and time to transformation to high-risk MDS or AML		Rate and time to transformation to high-risk MDS or AML
Progression-free survival		Progression-free survival
Overall survival from date of inclusion to death or date of last news		Overall survival from date of inclusion to death or date of last news
Exploratory criteria: factors associated with survival and response, including IPSS-R, karyotype and somatic mutations (IPSS-M)		Exploratory criteria: factors associated with survival and response, including IPSS-R, karyotype and somatic mutations (IPSS-M)

Trial Locations

Locations (3): Assistance Publique Hopitaux De Paris
🇫🇷
Paris, France
Centre Hospitalier Universitaire De Nice
🇫🇷
Nice, France
Institut Gustave Roussy
🇫🇷
Villejuif, France
Assistance Publique Hopitaux De Paris
🇫🇷Paris, France
Pierre FENAUX
Site contact
0033171207022
pierre.fenaux@aphp.fr